ANDROGEN RECEPTOR ANTAGONIST VERSUS AGONIST ACTIVITIES OF THE FUNGICIDE VINCLOZOLIN RELATIVE TO HYDROXYFLUTAMIDE
ANDROGEN RECEPTOR ANTAGONIST VERSUS AGONIST ACTIVITIES OF THE FUNGICIDE VINCLOZOLIN RELATIVE TO HYDROXYFLUTAMIDE
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DOI：
10.1074/jbc.270.34.19998
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发表时间：
1995-08-25
影响因子：
4.8
通讯作者：
WILSON, EM
中科院分区：
文献类型：
--
作者：
WONG, CI;KELCE, WR;WILSON, EM
利用重组人雄激素受体（AR）研究了烯氯唑啉（3-（3，5-二氯苯基）-5-甲基-5-乙烯基恶唑烷-2，4-二酮）的抗雄激素作用机制。在植物和哺乳动物中，乙烯菌核利的两种主要代谢物是M1（2-[[3，5-二氯苯基）-氨基甲酰基]氧基]-2-甲基-3-丁烯酸）和M2（3 '，5'-二氯-2-羟基-2-甲基丁-3-烯酰苯胺）。这两种代谢产物以剂量依赖性方式将AR靶向细胞核，并抑制雄激素诱导的小鼠乳腺肿瘤病毒启动子介导的反式激活。M2是比M1强50倍的有效抑制剂，仅比羟基芴醇低2倍。在双氢睾酮（50 nM）存在下，M2（0.2-10 μ M）抑制雄激素诱导的AR与雄激素反应元件DNA的结合。在不存在双氢睾酮的情况下，浓度为10 μ M的M2或羟氟沙星促进AR与雄激素反应元件DNA的结合和转录的激活。M2和羟基芴醇的激动剂活性在低10倍的浓度下发生，突变体AR（Thr（877）至Ala）是LNCaP人前列腺癌细胞内源性的。结果表明，雄激素拮抗剂可以作为激动剂，这取决于配体结合亲和力，浓度和竞争的天然配体的存在。
The mechanism of antiandrogenic activity of vinclozolin (3-(3,5-dichlorophenyl)-5-methyl-5-vinyloxazolidine-2,4-dione), a dicarboximide fungicide under investigation for its potential adverse effects on human male reproduction, was investigated using recombinant human androgen receptor (AR). The two primary metabolites of vinclozolin in plants and mammals are Mi (2-[[3,5-dichlorophenyl)-carbamoyl]oxy]-2-methyl-3-butenoic acid) and M2 (3',5'-dichloro-2-hydroxy-2-methylbut-3-enanilide). Both metabolites, in a dose-dependent manner, target AR to the nucleus and inhibit androgen-induced transactivation mediated by the mouse mammary tumor virus promoter. M2 is a 50-fold more potent inhibitor than M1 and only 2-fold less than hydroxyflutamide. In the presence of dihydrotestosterone (50 nM), M2 (0.2-10 mu M) inhibits androgen-induced AR binding to androgen response element DNA. In the absence of dihydrotestosterone, concentrations of 10 mu M M2 Or hydroxyflutamide promote AR binding to androgen response element DNA and activation of transcription. Agonist activities of M2 and hydroxyflutamide occur at 10-fold lower concentrations with the mutant AR (Thr(877) to Ala) endogenous to LNCaP human prostate cancer cells. The results indicate that androgen antagonists can act as agonists, depending on ligand binding affinity, concentration, and the presence of competing natural ligands.